2, 3-oxygenated-17alpha-methyl-5alpha-androstan-17beta-ols



3,169,134 2,3-XYGENATED-170t-METgIYL-50t-ANDROSTAN- 17 3-011 Paul D. Klimstra, Northbrook, 111., assignor to G. D. Searle & ('10., Chicago, 111., a corporation of Delaware N0 Drawing. Filed Mar. 21, 1963, Ser. No. 266,797

8 Claims. (Cl. 260-13914) The present invention relates to 2,3-dioxygenated derivatives of 17zx-methyl-5a-androstan-17/3-01. That is, it relates to compounds wherein the 2 and 3-positions are occupied by substituents such as 0x0, hydroxy, methoxy, and, (lower alkahoyD-oxy. More particularly, 'it relates to compounds of the formula wherein Y is selected from the group consisting of methoxy and (lower ankanoyl)oxy and Z is selected from the group Consisting of e-hydroxymethyleneand carbonyl; the invention also relates to compounds of the formula CH3 "CH3 wherein Y 'is selected from the group consisting of 13 -hydroxymethylene and carbonyl and Z"i s selected from the group consisting of methoxy and (lower alkanoyl) oxy. Thus, it will be obvious that the 2 and 3-substituents are selected in such a manner that one of them is hydroxy or 0x0 While the other is methoxy or (lower alkanoyl) oxy.

The lower alkanoyl radicals referred to above contain up to six carbon atoms and are exemplified by radicals such as acetyl, propionyhbutyryl, pentanoyl, and

' hexanoyl.

other hand, if the 25,3;3-epoxide is heated with methanol in the presence of a trace of acid, 3ot-methoxy-l7ot-methyl- Sa-andrOstane-Ze,17,8-diol is obtained. When the 2a,3tzepoxide is used as a starting material, heating with a lower alkanoicacid gives the corresponding Zfi-(lower alkan oyl)oxy-17ot methyl-5ot-androstane-30:,175 diol, whereas heating with methanol in the-presence ofa trace of sulfuric acid gives ZB-methoxy-17a-methyl-5 t-androstane- 3a,l75-diol.

The androstan-3a-o1s, substituted'in the file-position with States Patent methoxy or (lower alkanoyDoxy, can be converted to the corresponding androstan-3-one by oxidation. The same procedure can be used to prepare the androstan-Z- ones from the corresponding Zfi-hydroxy compounds. A favored oxidizing agent for this purpose is a solution of chromium trioxide in sulfuric acid.

An alternate approach to the preparation of the methoxy compounds of the present invention makes use of the 2,3-ep0xy-5a-androstan-l7-ones. Treatment of the ZBJfl-epoxide with methanol in the presence of acid gives 2,8-hydroxy-3u-methoxy-5a-androstan47-one whereas reaction of the :,3oL-CPOXY compound with the same reagent gives 3a-hydroxy-2,B-methoxy-5a-androstan-17-one. Either of these monomethoxy compounds can then be reacted with an excess of methylmagnesium bromide to give the corresponding 2,8,3ot-disubstitut'ed-l7u-methyl-5a- 'androstan-17 8 o1.

The compounds of the present invention are useful be-.

cause of their valuable pharmacological properties. They are, for example, anti-estrogenic agents as is evidenced by their ability to inhibit estrogen-stimulated biological responses.

The invention will appear more fully from the examples which follow. These examples are set forth by Way of illustration only, and it will be understood that the invention is not to be construed as limited in spirit or in scope'by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples, temperatures are given in degrees centigrade 0.). Quantities of materials are expressed in part by weight unless otherwise noted.

Example 1 Example 2 A solutionof 2 parts of 2fi,3fi-epoxy-17a-methy1-5u- \androstan-l7B-ol in 262 parts of glacial acetic acid is heated on a steanibath for 5 hours. The resultant mixture is poured into ice water whereupon an amorphous solid forms. The solid is separated and the aqueous portion is extracted with ether. The solid is combined with the ether extracts and the resultant solution is washed, first with water and then with 5% sodium bicarbonate solution, and dried over anhydrous potassium carbonate and characoal. The solvent is removed from the solution under reduced pressure to leave a solid which is recrystallized froma mixture of acetone and hexane to give 304 acetoxy 17oz methyl-5a-androstane-ZB,l7B-diol, melting at about 193-l95 C.; [a] =l21 (chloroform). This compound has the following formula "7) 3 Example 3 If an equivalent quantity of propionic acid is substituted for the acetic acid and the procedure of Example 2 is repeated, the product is 3a-propionoxy-lh-methyl- Sa-androstane-Zfl,l7fi-diol. The compound has the following formula CH CH COO Example 4 .To a solution of 2 parts of Boa-acetoxy-17a-methy1-5aandrostane-2fl,l7,8-diol in 32 parts of acetone is added portionwise, with stirring, an aqueous solution which is 8 N in chromium trioxide and 8 N in sulfuric acid. The addition is continued until the brown color persists and then. the excess chromium trioxide is destroyed by the addition of afew drops of 2-propanol. The resultant solution is decantedfrom the precipitated salts and into water and cooled. A precipitate forms and this is filtered, washed with water, and air dried. The solid is recrystallized. from a mixture of acetone and n-hexane to give 3ot-acetoxy-l7 a-methyl-17p-hydroxy-5a androstan-Z-one melting at about 172-175" C.; [a]' =+35 (chloroform). This compound has the following formula on C33 "-0113 OH ona INCH:

Example 6 To a solution of 2.9 parts of 17a-methyl-5a-androst-2- en-l7 8-ol (Example 14, US. Patent 3,018,298) and 0.4 part of anhydrous sodium acetate in 112 parts of chloroform is added portionwise, with stirring and cooling, 4 parts by volume of 40% peracetic acid in acetic acid solu- This compound has the foltion. This reaction mixture is allowed to stand at room temperature for about 2 hours, and then is washed with dilute aqueous potassium hydroxide, dried over anhydrous sodium sulfate, and concentrated to dryness at reduced pressure. The residue is recrystallized from ethanol to give 2a,3a-epoxy-17a-methyl-5a-androstant-l75-01, melting at about 205-207 (3.; [a] =-H).5 (chloroform).

Example 7 A solution of 2 parts of 20:,3a-epoxy-l7a-methyl-5eandrostan-lm-ol and 32 parts of methanol containing 0.05 part of concentrated sulfuric acid is refluxed on a steam bath for 1.75 hours. The resultant solution is poured into parts of water containing 0.1 part of sodium bicarbonate. The precipitate which forms is separated, washed with water, and dried. It is then recrystallized froma mixture of acetone and hexane to give ZfJ-methoxy-lhmethyI-Sa-andIQstane-Ba,17/8-diol, melting at about 16"- C.; [a] =+6 (chloroform); This compound has the following formula on C 11% L H3 CHQO It Example 8 To a solution of 1.2 parts of 2fl-methoxy-17e-metn 5e-androstane-3e,17/3-diol in 16 parts of acetone is added portionwise, with stirring, an aqueous solution which is 8 N in chromium trioxide and 8 N insulfuric acid until the brown color persists; Excess chromium trioxide is destroyed by the addition of a few drops of 2-propanol. The liquid is decanted from the precipitate into ice water, and the resultant mixture is extracted with ether. The ether extract is washed first with 5% sodium bicarbonate solution and then with water and then dried over anhydrous potassium carbonate and charcoal. Removal of the solvent under reduced pressure leaves an oil which is dissolved in benzene and chromatographed on asilical gel column Elution with a 20% solution of ethyl acetate in benzene gives, after evaporation of the solvent, 17,6-hydroxy-Ztt-methoxy-17a-methyl-5 -androstane-S-one, melting at about 14-9-152 (3.; '[a],;,:+76.5 (chloroform).

This compound has the followingformula OH CH3 Example 9 A solution of 20 parts of 2a,3a-epoxy-l7ct-methyl-5e androstan-l7 3-ol in 525 parts of glacial acetic acid is heated on a steam bath for 4.5 hours. The resultant solution is concentrated under reduced pressure and the residue is poured into ice water. The amorphous solid which precipitatesis.separated, washed with 5% sodium bicarbonate solution and then with water. The solid is then dissolved in benzene and chromatographed on a silica gel column. Elution with a 25% solution of ethyl acetate in benzene gives, after evaporation of the solvent and recry talhzation of the'residue from a mixture of acetone and hexane, 2p-acetoxy-17ct-methyl-5a-androstane-B04,17fi-di0l,

melting at about 214-216.5 C. This compound has the following formula OH CH3 Example OH CH? GH3 013 000 Example 11 An equivalent quantity of propionic acid is substituted for the acetic acid and the procedure of Example 9 is repeated. This gives 2,6-propionoxy-17a-methyl-5mandrostane-3ot-l7j3-diol.

The ZB-propionoxy-17a-methyl-5u-androstane-30:,17/3- diol is oxidized with chromium trioxide in sulfuric acid according to the procedure described in Example 10. This gives 2p-propionoxy-17a-methyl-17B-hydroxy-5aandrostan-3-one. This compound has the following formula What is claimed is: l. A compound selected from the group consisting of compounds of the formula OH CH wherein Y is selected from the group consisting of methoxy and (lower alkanoyl)oxy and Z is selected from the group consisting of a-hydroxymethylene and carbonyl; and compounds of the formula wherein Y is selected from the group consisting of B-hydroxymethylene and carbonyl and Z is selected from the group consisting of methoxy and (lower alkanoyDoxy.

2. A compound of the formula (lower a1kanoy1)O-- 3. 3 a-acetoxy- 17a-methy1-5 oL-Ell'lClI'OSifiIlE-Zfi, l7p-dio1. 4. A compound of the formula 5. 2B acetoxy 17B hydroxy 17a methyl 50candrostan-3-one.

6. A compound of the formula (lower alkanoyl) 0- 7. ZB-acetoxy-17a-methyI-Sa-andrOstane-Ba,17B-diol. 8. 3a-methoxy-17a-methyl-5a-androStane-Zfi,17/3-diol.

References Cited in the file of this patent UNITED STATES PATENTS Julian et a1 Oct. 27, 1959 OTHER REFERENCES Kowk et al.: J. Org. Chem, vol. 28, p. 423-27, February 1963.

TED STATES PATENT ormcn QTIHCATE D1 CDEMWN Patent No 3,169,134 February 9,. 1965 Paul D. Klimstra It is hereby certified that'error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 34, for "3uI-ITHTHnLHTRARAT" read 3oe-bromg-l7 d-methyl-Soncolumn 3, line 31, for "-17 or" read -l7osame line 31, for "-500 androstan" read 5d-androstancolumn 4, line 6, for "-androstant" read androstan line 33, the indistinct word should be -methylcolumn 6 lines 54 to 64 the lower left-hand portion of the formula should appear as shown below instead of as in the patent:

Signed and sealed this 6th day of July 1965.

(SEAL) Attest:

Commissioner of Patents 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 